Several neurodegenerative diseases are recognized as disorders of abnormal protein conformation. Many of them arise from mutations that result in a protein with decreased conformational stability that prevents the normal folding or the association of the polypeptide with other subunits or stabilizing cofactors. We described a neurodegenerative disease characterized by the presence of intranuclear ferritin inclusion bodies associated with a novel mutation in the ferritin light chain (FTL) gene. We hypothesize that the mutation causes a major conformational change in the FTL polypeptide, leading to the abnormal accumulation of ferritin inclusion bodies and neurodegeneration. Our long-term objective is to define the structural basis and mechanisms that are implicated in the formation of ferritin inclusion bodies and in the neurodegenerative process. This work has far-reaching implications beyond this single gene disorder, since many other neurodegenerative diseases are also characterized by the presence of intranuclear inclusion bodies. Furthermore, these studies will increase our understanding of the consequences of the disruption of cellular iron metabolism in more common neurodegenerative diseases. In Specific Aim 1, we will determine the consequences of the mutation in the stability of the FTL subunit as well as in the assemble and functionality of ferritin. Detail biochemical analysis will provide the basis to understand the role of the mutation in the disease. In Specific Aim 2, we will determine the temporal and spatial patterns of ferritin deposition in brain tissues from transgenic mice and determine whether misregulation of iron metabolism in affected neurons is implicated as a cause of neurodegeneration. These studies will provide insights on basic pathological mechanisms. In Specific Aim 3, we will determine whether mutant ferritin gains a toxic function that is harmful to neurons. We will study the interaction between ferritin and nuclear proteins and the role of the ubiquitin-proteasome pathway in the abnormal accumulation of ferritin and in the pathogenesis of the disease.